tbuckley/cabot-search huggingface dataset:
Clinical and genomic characteristics between DDR germline and somatic mutations in pan-cancer.
Authors: Yanchun Li, Tingting Sun, Qin Zhang, Chuang Qi
Journal: Journal of Clinical Oncology (2023)

e15139 Background: The defects DNA-damage repair (DDR) genes would drive tumor formation and are associated with increased genomic instability and tumor mutational burden (TMB) in cancer. Although, alterations of DDR genes are common in tumor, the differences between the germline and somatic alterations are poorly characterized. Methods: The DNA sequencing data of 540 genes from 6174 pan-cancer patients were retrospectively collected and 276 DDR genes were analyzed. The variations were annotated as pathogenic (P), likely pathogenic (LP), and nonpathogenic (NP) according to ACMG (American College of Medical Genetics) guideline. The patients were divided into 3 groups: DDR-germline (P&amp;LP germline variants, N = 766), DDR-somatic group (only P&amp;LP somatic variants, N = 2923) and non-DDR group (NP variants, N = 2485). Results: In pan-cancer, 12.41% patients have germline DDR gene mutations, of which tumors with high germline mutation frequency include ovarian cancer (27/102, 26.47%), glioma (22/136, 16.18%), breast cancer (25/159, 15.72%), genitourinary cancer (17/114, 14.91%), biliary tract cancer (42/284, 14.79%), pancreatic cancer (28/193, 14.51%), colorectal cancer (95/727, 13.07%), head-neck tumors (11/85, 12.94%) and esophagus cancer (16/124, 12.90%). Meanwhile, 47.34% patients have somatic DDR gene mutations, of which tumors with high somatic mutation frequency include esophagus cancer (89/124, 71.77%), colorectal cancer (488/727, 67.13%), endometrial cancer (49/73, 67.12%), head-neck tumors (50/85, 58.82%), pancreatic cancer (111/193, 57.51%), gastric carcinoma (233/415, 56.14%), ovarian cancer (53/102, 51.96%) and biliary tract cancer (138/284, 48.59%). The most commonly germline alterations were found in TP53 (33%), PTEN (14%) and BRCA2 (14%), while in the somatic mutations, TP53 (52%) showed the highest frequency, PTEN (9%) and MSH3 (8%) followed. In pairwise comparisons of the three groups’ actionable mutations, DDR-somatic group was more likely to have alterations in TP53 (OR = 5.68), AKT3 (OR = 5.81) and APC (OR = 1.42) compared with DDR-germline group. Taken non-DDR group as reference, mutations in TP53 (OR = 5.09), PTEN (OR = 7.65), BRCA2 (OR = 5.32) were more common in DDR-germline group, but TP53 (OR = 28.90), PTEN (OR = 7.73), APC (OR = 2.68) in DDR-somatic group. The tumor mutational burden (TMB) was statistically different among the three groups (p &lt; 2.22e−16). The DDR-somatic group exhibits the highest median TMB (5.68) compared with 1.42 in DDR-germline and 2.13 in non-DDR group. Conclusions: The differences in the mutation profile between the DDR-germline and DDR-somatic groups and the distinct actionable genes may indicate the different target-therapy choices. Besides, DDR-somatic group exhibited the highest TMB, which might indicate patients with somatic DDR alterations may better benefit from the immunotherapy.
PD-L1 expression in patients with multiple tumors and their correlation with genomic mutations.
Authors: Guomin Lin, Shaohua Yuan, Fei Pang
Journal: Journal of Clinical Oncology (2023)

e15152 Background: Immune checkpoint inhibitors (ICIs) is effective in treating tumors expressing PD-L1, however, the reported response rate was low. Inter-tumoral heterogeneity might be one of the reasons for the insensitive of ICIs. In patients with multiple tumors (defined as co-occurrence of more than one malignant lesion in a single or multiple sites), the situation is more complicated. Methods: A total of 67 patients who provided tumor tissues from at least two anatomical sites for assessment of PD-L1 expression by immunohistochemistry (22C3 and/or 28-8 antibodies) was enrolled in this study. Cells with ≥1% staining was defined as a positive result. The sequencing data of 61 patients was also retrospectively reviewed. Targeted sequencing was performed with panels of up to 450 cancer-related genes (at least 47 genes in common). Matched peripheral blood samples were also tested as control to exclude germline mutations. Results: At sample level, the PD-L1 positivity by cancer type was as follow: cervical cancer/melanoma/adrenal gland carcinoma (100% [1/1]), thymic cancer (100% [5/5]), colorectal cancer (80% [8/10]), esophageal squamous cell carcinoma (62% [8/13]), ovarian cancer (57% [4/7]), biliary tract cancer (50% [3/6]), lymph node metastasis (50% [1/2]), pancreatic cancer (50% [2/4]), lung squamous cell carcinoma (43% [3/7]), endometrial cancer (40% [4/10]), breast cancer (29% [2/7]), gastric cancer (25% [2/8]), lung adenocarcinoma (15% [4/26]) and liver cancer (14% [1/7]). All the provided tissues were positive or negative for PD-L1 in 42 patients and were partly positive and partly negative in 25 patients. At patient level, differentially mutated genes between the two above-mentioned groups of patients included CCND1 (10.5% vs 39.1%, P = 0.0116), FGF19 (7.9% vs 30.4%, P = 0.0324), FGF3/4 (7.9% vs 34.8%, P = 0.0143) and TERT (21.1% vs 0%, P = 0.0199). Tumor mutation burden and microsatellite instability status were comparable between the two groups. Consistent with previously reported (not specifically recruiting patients with multiple tumors), EGFR exon 19 deletion was preferentially mutated in PD-L1 negative tumors (16.7% [4/24] vs 0% [0/7], P = 0.5497) in non-small-cell lung cancer, and PD-L1 expression was correlated with EGFR wild-type (wild-type: 75% [3/4] vs mutated: 45% [9/20], P = 0.5901) and ALK mutation (mutated: 25% [1/4] vs wild-type: 5% [1/20], P = 0.3116) in lung adenocarcinoma, although statistical significance was not reached. Conclusions: For patients with multiple tumors, inter-tumoral heterogeneity of PD-L1 expression is common. Several actionable gene mutations were found to be more commonly occurred in PD-L1-heterogenous tumors. Physicians should carefully consider PD-L1 and genomic assessments by case in order to select appropriate patients for ICI treatments.
Tumor immune environment in colitis-associated colorectal cancers: Comparison with sporadic colorectal cancers.
Authors: Wenliang Li, Ning Xu, Fengchang Huang, Kun Yu, Quan Yang
Journal: Journal of Clinical Oncology (2023)

e15531 Background: Persistent inflammatory diseases such as ulcerative colitis (UC) and Crohn’s disease (CD) contribute to the tumor initiation and progression in colitis-associated cancers (CAC). Intestinal damage caused by persistent inflammation promotes clonal expansion of somatic and epithelial cells and alters the immune microenvironment. A comprehensive investigation in comparing the tumor immune environment in CAC with sporadic colorectal cancers (CRC) will provide more clinical usefulness of immunoprofiling in CRC. Methods: Thirteen patients with CAC (6 with UC and 7 with CD) and 10 patients with sporadic colorectal cancer from our hospital were enrolled in the study. FFPE samples from patients were analyzed for the tumor infiltrating lymphocytes [PD-L1+, CD3+, CD4+, CD8+, CD20+, CD68+, CD163+] by multiplex immunofluorescence technique. The core and peritumor areas annotated by pathologists on images. Then artificial intelligence (AI) algorithms delineated the tumor-enriched segments and stroma, and calculated the density and percentage of each marker in two regions. A nonparametric approach (Kruskal–Wallis) was used to compare the density and percentage of immune cells between CAC and sporadic colorectal cancer groups. Results: In the stroma area, the density (counts per mm 2 ) of PD-L1+CD68+ cells in patients with CAC were significantly higher than those in sporadic cancer patients (p &lt; 0.05). However, the density of PD-L1+CD68+ did not show significant differences related to disease types (CAC or sporadic CRC) in the tumor-enriched segments. Significantly, the density of CD3+CD4+ cells and the percentage of CD68+CD163- cells in patients with CAC showed a trend of higher density than those in sporadic cancer patients in the stroma area (all, 0.05 &lt; p &lt; 0.1). The density and the percentage of CD20+ cells in CAC patients had a higher density tendency than those in sporadic cancer patients both in the tumor-enriched segments and stroma (all, 0.05 &lt; p &lt; 0.1). Other indicators in tumor-enriched segments and stroma, such as CD3+, CD4+, CD8+, CD68+CD163+ and PD-L1+, had no significant difference between CAC and sporadic CRC patients, regardless of the percentage or the density. Conclusions: We identified that the tumor immune environment of CAC was different from that of sporadic CRC. Some tumor infiltrating lymphocytes such as PD-L1+CD68+ cells infiltrated more in CAC than those in sporadic cancer, suggesting that CAC may respond better to immunotherapy than sporadic CRC. However, this hypothesis requires a further validation with a larger sample size.
Neoadjuvant tislelizumab plus chemotherapy for resectable locally advanced esophageal squamous cell carcinoma (ESCC): Interim analysis of a phase 2 study.
Authors: Na Zhuo, Wei Qiu, Jia He, Li Li, Qiang Wang, Shuangni Yu, Wei Liu, Lin Zhao, Chunmei Bai
Journal: Journal of Clinical Oncology (2023)

e16087 Background: Esophageal cancer (EC), as the sixth most frequently diagnosed cancer and the fourth leading cause of cancer death, poses a major health threat in China. Neoadjuvant treatment is recommended for resectable diseases with high recurrent risks; however, benefits with platinum-doublet chemotherapy are modest. Although the addition of tislelizumab, a anti-PD-1 antibody to chemotherapy has shown survival benefit in unresectable or metastatic EC, data are lacking to support such combination as a neoadjuvant modality. Here, we report the interim analysis of efficacy and safety of a prospective, phase 2 clinical trial evaluating tislelizumab plus chemotherapy as neoadjuvant treatment for locally advanced ESCC. Methods: Adults with clinical stage II-IVA (T3-T4 and/or node positive), potentially resectable ESCC, ECOG PS 0-1, and no known PD-1 expression were enrolled to receive tislelizumab (200mg) plus chemotherapy (docetaxel 75mg/m 2 plus cisplatin 75mg/m 2 or carboplatin AUC = 5 if CCr &lt; 60ml/min) every 3 weeks for 4 cycles. Adjuvant tislelizumab up to 9 months were optional according to patients’ will. The primary endpoint was pathological complete response (pCR). Secondary endpoints include R0 resection, disease free survival (DFS), adverse events (AE), and biomarkers for predicting efficacy. Results: Between November 11, 2020 and Feburary 10, 2023, 28 patients with clinical stage III (n = 13) or IVA (n = 15) diseases were enrolled. 27 completed neoadjuvant treatment and 5 withdrew early because of disease progression (n = 2), serious AEs (n = 2) and bronchoesophageal fistula (n = 1). 21 patients underwent McKeown MIE and 20 (95.2%) acheived R0 resection. One patient was awaiting surgery. pCR (ypT0N0) was achieved in 33.3% (7/21) patients. According to the CAP tumor regression grading system, 3 (14.3%) cases were categorized as grade 1, 7(33.3%) were categorized as grade 2 and 4 (19%) were categorized as grade 3 in primary tumor. Most treatment related AEs (TRAEs) during neoadjuvant setting were mainly of grade 1 or 2. Grade 3 or 4 TRAEs occurred in 37.0% patients (10/27) and 14.8% (4/27) was considered immune-related. Surgical complications of any grade occurred in 4 patients (19.0%), 3 of which were grade 3. No grade 5 events were noted. 14 (66.7%) patients were able to continue adjuvant tislelizumab after surgery. Conclusions: Neoadjuvant tislelizumab plus chemotherapy has achieved encouraging pCR rate and tolerable safety activity in this study. Clinical trial information: ChiCTR2100043772 .
Transcriptomic heterogeneity of metastatic disease timing within metastatic castration-sensitive prostate cancer.
Authors: Philip Sutera, Amol Shetty, Alexander K. Hakansson, Kim Van der Eecken, Yang Song, Yang Liu, Valerie Fonteyne, Sofie Verbeke, Daniel Y. Song, Ashley Ross, Felix Y Feng, Silke Gillessen, Gerhardt Attard, Nicholas D. James, Tamara L. Lotan, Elai Davicioni, Christopher Sweeney, Phuoc T. Tran, Matthew Pierre Deek, Piet Ost
Journal: Journal of Clinical Oncology (2023)

e17083 Background: Metastatic castration-sensitive prostate cancer (mCSPC) is commonly partitioned into high- and low-volume subgroups which have demonstrated differential biology, prognosis, and response to therapy. Timing of metastasis has similarly demonstrated differences in clinical outcomes, however less is known about any potential underlying biologic differences between these disease states. Herein we aim to compare transcriptomic differences between synchronous and metachronous mCSPC and identify any differential responses to therapy. Methods: We performed an international multi-institutional retrospective review of men with mCSPC who completed RNA expression profiling evaluation of their primary tumor. Patients were stratified according to disease timing (synchronous vs metachronous). The primary endpoint was to identify differences in transcriptomic profiles between disease time. Median genomic scores between groups were compared with Mann-Whitney U test. Secondary analyses included determining clinical and transcriptomic variables associated with overall survival (OS) from time of metastasis. Survival analysis was performed with the Kaplan-Meier Method and Multivariable Cox regression. Results: 252 patients were included with a median follow-up of 39.6 months. Patients with synchronous disease experienced worse 5-yr OS (39% vs 79%, p&lt;0.01) and demonstrated lower median Androgen Receptor Activity (AR-A) (11.78 vs 12.64, p&lt;0.01) and Hallmark Androgen Response (HAR) (3.15 vs 3.32; p&lt;0.01). Multivariable cox-regression identified only high-volume disease (HR=4.97, 95%CI 2.71-9.10; p&lt;0.01) and HAR score (HR=0.51, 95%CI 0.28-0.88; p=0.02 significantly associated with OS. Finally, patients with synchronous (HR=0.47, 95%CI 0.30-0.72; &lt;0.01) but not metachronous (HR=1.37, 95%CI 0.50-3.92; p=0.56) disease were found to have better OS with Androgen Receptor (AR) + non-AR combination therapy as compared to monotherapy (p value for interaction = 0.05). Conclusions: We have demonstrated a potential biologic difference between metastatic timing of mCSPC. Specifically, for patients with low volume disease, those with metachronous low volume disease have a more hormone dependent transcriptional profile and exhibit a better prognosis than synchronous low volume disease. [Table: see text]
TCR-T cells armored with immune checkpoint blockade in EBV-positive nasopharyngeal carcinoma: The first-in-human phase 1/2 trial.
Authors: Qingzhu Jia, Ling Peng, Gang Chen, Haiyang Wu, Dong Zeng, Tao Liu, Yunpeng Zhan, Si Li, Frank Su, Bo Zhu, Qi-Jing Li
Journal: Journal of Clinical Oncology (2023)

6047 Background: Nasopharyngeal carcinoma (NPC) refraction and metastasis is common, but therapeutics are limited. As adoptive immunotherapy has emerged as effective against other cancers, engineered T cells bearing a transgenic Epstein-Barr virus (EBV)-specific TCR (TCR-T) represent a viable approach to treat EBV-associated NPC. Given PD-1/PD-L1 induced T cell hypofunction, we herein report preliminary findings of a phase I trial of EBV-targeting TCR-T cells armored with secreted PD-1 blockade for patients who failed in two or more lines of standard therapies. Methods: Patients with advanced NPCs were consented and screened for EBV serotype and HLA haplotype. EBV+/HLA-A*02+ patients were enrolled in a rapid titration setting to escalate the single infusion dose from 5x10 6 to 1.0x10 7 and 5.0x10 7 /kg TCR-T cells. After safety evaluation, the 5.0X10 7 /kg cohort was expanded for further investigation of combining with IL-2 administration. Fludarabine/cyclophosphamide were administered prior to TCR-T cell transfer as pre-conditioning. Patient monitoring and peripheral blood analysis occurred weekly over the first month and then monthly until disease progression or patient withdrawal. The primary objective was to determine safety and a recommended phase 2 dose (RP2D), while the secondary objective was investigator assessed ORR (RECIST v1.1). Results: One patient per TCR-T dose was treated, and, as no dose-limiting toxicity (DLT) has been observed, dose level 3 (5.0x10 7 /kg) was expanded with IL-2 administration upon TCR-T cell infusion. As of January 2023, six patients have been treated. One patient (16.7%) exhibited grade 1 CRS (n=6). No grade 4 treatment-related adverse events (TRAEs) have been observed, with leukopenia and fever being the most common AEs. Two patients (33.3%) were assessed as partial response (PR), with one reaching a response duration of 9 months to date. Three patients (50%) were assessed as stable disease (SD). For all patients, pharmacokinetic analysis revealed that levels of TCR-T cells in peripheral blood peak between 3- and 14-days post-infusion, with a maximum duration of 180 days. Conclusions: EBV-targeting TCR-T cells armored with PD-1 blockade are well tolerated. Initial results from this ongoing study indicate that EBV proteins may be safe and effective TCR-T targets to achieve superior outcomes in advanced EBV-positive NPC patients. Clinical trial information: NCT04139057 . [Table: see text]
Androgen-deprivation therapy and risk of dementia in patients with prostate cancer: Clinical outcomes from real-world data.
Authors: Dina Elantably, Jiasheng Wang, Abdul Rahman Al Armashi, Anas Al Zubaidi, Akram Alkrekshi
Journal: Journal of Clinical Oncology (2023)

5086 Background: Androgen deprivation therapy (ADT) is the cornerstone for the treatment advanced prostate cancer. However, there has been growing concerns regarding increased risk of dementia with ADT. Previous studies of dementia risk following ADT were controversial and inconclusive. Methods: Data was collected from an electronic health record database (TriNetX LLC., Cambridge, MA) which includes over 89 million patients from 56 healthcare systems in the United States. We identified males over the age 50 years who were diagnosed with any stage of prostate cancer between 2005 and 2022. Patients receiving ADT were 1:1 propensity score-matched with non-exposed controls for demographics and risk factors for dementia; diabetes mellitus, hypertension, hyperlipidemia, obesity, depression, cerebrovascular disease, tobacco use, alcohol dependence and benzodiazepine use. Patients with prior dementia, stroke, or TIA were excluded. Results: In a cohort of 627,025 men with prostate cancer, 73,933 patients (mean age of 70.8 years) received ADT and 57,005 patients (mean age of 70.4 years) did not. ADT exposure was associated with a diagnosis of dementia (Alzheimer’s disease, vascular dementia, or unspecified dementia); HR 1.6; 95% CI (1.49, 1.73). Subgroup analysis by dementia subtype is highlighted in (table). Compared to non-ADT group, exposure to ADT was associated with a statistically higher risk of dementia among whites (78.6% vs. 77.7%, P &lt;0.001), whereas there was no significant difference among African Americans. The risk of dementia with different ADT regimens is shown. Conclusions: This is the largest real-world study describing the association between ADT and the risk of dementia, including over 600 thousand prostate cancer patients. The risk of dementia was significantly higher in patients on ADT, with a 60% increased risk. The highest risk was witnessed with GnRH antagonists (degarelix), with a 92% increased risk. Interestingly, the increased risk of dementia in ADT groups was observed only among whites but not in African Americans. Possible causes of this discrepancy include socioeconomic disparities, bias that resulted in underdiagnosis, or biological differences. [Table: see text]
Screening mitophagy-related lncRNAs based on WGCNA to identify and validate a prognostic signature for patients with ovarian cancer.
Authors: Jianfeng Zheng, Yang Sun
Journal: Journal of Clinical Oncology (2023)

e17554 Background: Mitophagy refers to the process by which cells selectively remove incomplete or damaged mitochondria through the autophagic mechanism. However, the value of mitophagy-related genes (MRGs) and mitophagy-related lncRNAs (MRLs) in ovarian cancer (OC) is still not clear. Methods: We explored the alterations of MRGs in four gynecological tumors using R packages. Based on weighted coexpression network analysis (WGCNA), MRLs were identified to carry out LASSO Cox regression analysis and then we established the prognostic MRL-signature. The prognosis and independent prognostic value of the MRL-signature was also validated by four independent datasets from GEO. The expression level of MRLs involved in the prognostic signature we established were detected by qPCR for the samples we collected. Analysis for characteristics of functional pathways, immunity status, and anti-tumor therapy were based on GSEA, ssGSEA, CIBERSORT, xCELL, MCPcounter, ESTIMATE, and TIDE. The ceRNA network was constructed applying miranda, miRWalk3.0, and Cytoscape. Results: Most MRGs were found at lower expression levels in four gynecological tumors. Among the four gynecological tumors, the levels of CNV and MRGs were positively correlated. Most MRGs were negatively correlated with methylation level. A total of 52 MRGs were differentially expressed in OC tissues. Nine MRLs were significantly associated with survival prognosis. Eight optimal lncRNA combinations were screened by LASSO Cox Regression algorithm. On the basis of Univariate Cox regression and Multivariate Cox regression analyses, the risk model based on MRLs was proved to be the independent prognostic factors. The qPCR assay showed that the differential expression trends of these MRLs in our collected OC samples were consistent with those in TCGA database. We found that TIDE score of OC patients with lower risk score was lower, suggesting that OC patients with low RSs are more sensitive to immune checkpoint blockade therapy. OC patients with higher risk score had higher immune cell scores and higher risk score correlated strongly with higher stromal and estimated scores, while lower risk score correlated with tumor purity. We found that the IC50 levels of paclitaxel and ABT.888 (Veliparib) in the high-risk group were observably higher than those in the low-risk group, suggesting a negative correlation between risk score and the drug susceptibility of OC. There were 539 miRNAs, 73 mRNAs and 8 lncRNAs in the ceRNA network. Conclusions: The integrative analysis of MRGs and MRLs revealed their roles in prognosis and therapeutic responsibility in chemotherapy and immunotherapy. Our findings demonstrate the important clinical significance of the signature based on MRLs, and will help improve clinical outcomes for patients with OC.